Neurology and The Older Adult Ericka L. Crouse, PharmD, BCPP, BCGP, FASHP Virginia Commonwealth University Health System Learning Objectives At the conclusion of this application-based activity, participants should be able to: 1. List the common causes of mental status changes seen in older adults with delirium. 2. Select appropriate treatment for targeted symptoms in delirium. 3. Identify the key monitoring parameters for antiepileptic drugs. 4. Evaluate a given antiepileptic regimen in an older adult for efficacy and toxicity.
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Neurology and The Older Adult
Ericka L. Crouse, PharmD, BCPP, BCGP, FASHPVirginia Commonwealth University Health System
Learning ObjectivesAt the conclusion of this application-based activity, participants should be able to:
1. List the common causes of mental status changes seen in older adults with delirium.
2. Select appropriate treatment for targeted symptoms in delirium.
3. Identify the key monitoring parameters for antiepileptic drugs.
4. Evaluate a given antiepileptic regimen in an older adult for efficacy and toxicity.
The 3 D’s of Geriatric Psychiatry
Delirium
Depression
Dementia
Delirium
• Present in up to 50% of hospitalized elderly• On admission present in 8-17% of all elderly and
40% of nursing home (NH) residents• Associated with poor outcomes
Causes of Altered Mental Status***Often multi-factorial***
Duration and Causes of Delirium
• Prospective 2 year study in a 650 bed extended-stay geriatric medical center in N = 322 patients
• Delirium found in 34% (n = 109)
• Causes• 58% infection
• 36% metabolic
• 18% drug-induced
Arinzon Z, et al. Arch Geron & Geriatr 2011;52:270-5.
Infection
Urinary Tract Infection• Know your local sensitivities• Increasing resistance to SMZ/TMP and
fluoroquinolones • Psychiatric adverse effects of antibiotics• Nitrofurantoin updated on Beers list
Respiratory Infection
Wound Infection
Case Vignette
A 90 + year old female with dementia is referred from her NH for increasingly agitated behavior over the last week. She has developed a cough and is complaining of back pain. She was hospitalized within the last week for syncope. What do you recommend?A. Chest X-ray and urinalysis to rule out infectionB. Initiate an antibioticC. Start scheduled ibuprofenD. Start scheduled acetaminophenE. Start olanzapine 2.5 mg at bedtime
Respiratory Infection
This patient was transferred with an rx for levofloxacin 250 mg daily for pneumonia. She weighs ~ 45 kg; her SCr is 0.87 mg/dL [76.9 umol/L] and Cr/Cl 26 mL/min. Allergy to sulfa.
Which is the MOST appropriate dosing recommendation?A. Levofloxacin 250 mg daily
B. Levofloxacin 500 mg daily
C. Levofloxacin 750 mg daily
D. Levofloxacin 500 mg every other day
E. Levofloxacin 750 mg every other day
Urinary Tract Infection + Pneumonia
What do you recommend?A. Amoxicillin 500 mg every 8 hoursB. Amox/Clavulanate 500 mg every 12 hoursC. Amox/Clavulanate 875 mg every 12 hoursD. Vancomycin 1 G every 12 hoursE. Vancomycin 750 mg every 48 hours
Urine Culture
= sensitive= not synergistic= synergistic = sensitive
MIC interpretation
MIC= minimum inhibitory concentration
Dehydration
Look for symptoms of dehydration• Reduced urination or urine output• Dry cracked lips• Skin tenting
In US units the BUN:SCr ratio of > 20:1 is considered pre-renal and can be associated with dehydration; however at baseline elderly may have an elevated BUN:Cr ratio secondary to reduced muscle mass
Electrolyte/Metabolic Imbalances
Hypercalcemia
Hyperglycemia (Diabetic ketoacidosis)
Hyperparathyroidism
Hyperkalemia
Hypernatremia
Metabolic acidosis
Hypoglycemia
Hypokalemia
Hyponatremia
Aldemir M, et al. Crit Care 2001;5:265Weiner M, et al. Yale J Biol Med 1970;43:76-109
Case Vignette – Hyponatremia and Altered Mental Status (AMS)
mEq
/L
An 80+ year old patient with a history of schizoaffective disorder on an antipsychotic +
For elderly patients• Lorazepam is preferred• Chlordiazepoxide and diazepam are more likely to
accumulate with their long t1/2 and active metabolites• These agents have in clearance by at least 50% and a 4-9x in
half-life elimination
• Role of Thiamine?
Peppers MP. Pharmacotherapy 1996;16(1):49-58
Benzodiazepine Withdrawal
• Benzodiazepine withdrawal depends on the half-life of the medication
• Some present as early as 3 days after discontinuation others up to 2 weeks later
• Case Example – A 63 yo male presented as a Trauma –his home diazepam 5 mg TID PRN did not have this restarted on admission. • On ~ day 10 or 11 started exhibiting agitated intrusive
behaviors, increased anxiety, 0-2 hours of sleep. Was very disoriented and wandering in hall. Noted to be having auditory, visual, and tactile hallucinations.
• Agitation and orientation improved with lorazepam • Diazepam half-life is 44-48 hours; metabolite ~ 100 hours
• Time to get out of system – 10 to 20 days and symptoms of withdrawal to begin
Delirium-inducing Medications
Anti-cholinergics
Opioids
Sedative/
Hypnotics
Case Vignette - Drug toxicity75 + year old female with history of Neurocognitive disorder, depression, DM2, HTN, and chronic pain brought to ED for Altered Mental Status. Over last 2 weeks has had major changes including staying in bed all the time, poor sleep, appears confused intermittently, + auditory hallucinations of hearing angels, + visual hallucinations of seeing birds in the room and people in the room.
Symptoms appear even worse over the last 2 days. Other complaints include back pain (from arthritis) and a recent fall (X-ray negative for fracture). Denies constipation.
• Salahudeen MS, et al. completed a systematic reviews of Anticholinergic Burden/Scoring Scales• Identified 7 Anticholinergic Burden/Scoring Scales from
4 different countries• USA - Carnahan 2006 Anticholinergic Drug Scale identifies 117
anticholinergic medications
• Reviewed consistency between scoring of each scale
• Example quetiapine was rated high n = 1, moderate n = 1, low n = 2 scales
Salahudeen MS, et al. BMC Geriatrics 2015;15:31
Beers List Delirium
• Meds that are potentially inappropriate: • Antipsychotics (APs), anticholinergics,
Treat acute medical issues Infection, rehydration, hypoxia
Reorientation Eyeglasses, hearing aids, etc…
Safe mobility Early mobilizationAvoid restraints
Sleep-wake cycle (without use of sedatives) Provide uninterrupted sleep Reduce daytime nappingConsider earplugs
Pharmacological Management Severe agitation - Low doses of antipsychotics (e.g.haloperidol 0.25-0.5 mg PO or IM BID or atypical antipsychotics)ETOH Withdrawal – Benzodiazepines
Inouye SK, et al. Lancet 2014;383:911-22.
SCCM Guidelines 2013
• No Evidence
Does haloperidol treatment reduce duration of delirium?
• Small (n=36), prospective, randomized, double-blind study – quetiapinereduced duration of delirium
• SGAs may reduce duration of delirium [Evidence Level C]
Does SGA treatment reduce duration of delirium?
• NO. Trial (n = 104) trial was stopped early secondary to rivastigmine-treated patients experiencing more severe and longer delirium and trended towards higher mortality [Evidence Level 1B]
Should cholinesterase inhibitors be used in delirium
SCCM = Society of Critical Care Medicine; SGA = Second Generation Antipsychotic
Barr J, et al. Crit Care Med 2013;41:263-306.
Meta-Analysis of Antipsychotics in Delirium• Meta-Analysis of 19 studies (n = number of trials)
• N = 7 Post-op prevention with antipsychotic vs placebo• Haloperidol (n = 4) 1 – 7.5 mg/day• Risperidone (n = 2) 1 mg/day• Olanzapine (n = 1) 5 mg/day
• N = 12 Treatment Intervention (medical or surgical admissions; ICU [n = 5])• Haloperidol (n = 9) 0.75 mg – 20 mg/day• Ziprasidone (n = 1) 40 mg every 6 hrs• Risperidone (n = 2) 0.25 – 4mg/day• Quetiapine (n = 2) 25 – 400 mg/day• Control groups included placebo, risperidone, olanzapine (1.25 – 20 ng/day) or quetiapine
Neufeld KJ, et al. JAGS 2016;64:705-714.
Meta-Analysis Results
Outcome Results 95% CI
Post-Operative Prevention (n = 170)
No significant association with antipsychotic (AP) administration and incidence of delirium
OR 0.56, CI= 0.23 –1.34, I2=93%
Duration (n = 581) Severity(n = 464)
AP administration was not associatedwith a difference in duration or severity- Mean difference in duration (-0.65 days)- Mean difference in severity (-0.11)
CI= -1.59-0.29, I2=80%CI= -0.43-0.22, I2=61%
Hospital LOS(n = 1454)ICU LOS (n = 1400)
AP administration was not associatedwith a reduction in length of stay (LOS)- Hospital mean difference -0.01 days- ICU mean difference -0.46 days
CI= -0.16-0.14, I2=42%CI= -1.15-0.24, I2=91%
N = number of participants; OR = Odds Ratio; CI = 95% confidence interval; LOS = length of stay; ICU = intensive care unit
Neufeld KJ, et al. JAGS 2016;64:705-714.
Meta-Analysis Results
Outcome Results 95% CI
Post-Operative Prevention (n = 170)
No significant association with antipsychotic (AP) administration and incidence of delirium
OR 0.56, CI= 0.23 –1.34, I2=93%
Duration (n = 581) Severity(n = 464)
AP administration was not associatedwith a difference in duration or severity- Mean difference in duration (-0.65 days)- Mean difference in severity (-0.11)
CI= -1.59-0.29, I2=80%CI= -0.43-0.22, I2=61%
Hospital LOS(n = 1454)ICU LOS (n = 1400)
AP administration was not associatedwith a reduction in length of stay (LOS)- Hospital mean difference -0.01 days- ICU mean difference -0.46 days
CI= -0.16-0.14, I2=42%CI= -1.15-0.24, I2=91%
N = number of participants; OR = Odds Ratio; CI = 95% confidence interval; LOS = length of stay; ICU = intensive care unit
Overall Conclusion: Insufficient evidence to support routine use of antipsychotics for delirium prevention or treatment in hospitalized adultsStrength:Most comprehensive review of published dataWeakness: Heterogeneity of outcome measures
Neufeld KJ, et al. JAGS 2016;64:705-714.
Role of Antipsychotics?
• Severe agitation risking patient safety• Example post op and not following movement
restrictions
• Pulling out essential lines
• Psychotic symptoms causing severe distress
• If indicated• Lowest possible dose
• Short therapy (days)
Case Vignette
78 yo female with osteoporosis and hypertension admitted following a fall requiring hip replacement surgery. Day 5 post-op develops “confusion” and is tearing out IV lines and keeps trying to get out of bed and stand on hip.
• Work-up mostly negative – CXR and U/A negative. Not dehydrated. Electrolytes normal. Requesting a PRN for agitation to help calm her down.
Do you suggest?A. Lorazepam 0.5 mg IV
B. Quetiapine 25 mg PO
C. Ziprasidone 10 mg IMD. Risperidone 0.5 mg IM
E. Haloperidol 0.25 mg IV
Anticholinergic Activity of Antipsychotics
Haloperidol
Risperidone
Ziprasidone
Quetiapine
Olanzapine
Chlorpromazine
Clozapine
Antipsychotic Dosing PRN Delirium
Medication Dosage form
Route Onset/Time to peak
Initial PRN Frequency Comments
Haloperidol Tab, PO solution,Injection
POIM*IV
30 – 60 mins PO/IM/IV0.25 mg0.5-2 mg
Every 4 – 6 hrs *IV increaseQTc risk
Olanzapine TabTab-ODTInjection
POIM only
~ 4 hrs*15-45 mins
PO: 2.5 mg IM: 5 mg
Every 6 hrsMax IM 30 mg/day
**Do not combine with benzos
Risperidone Tab, PO solution
PO ≤ 60 mins PO: 0.25-0.5 mg
Every 6 hrs
Quetiapine Tab,Tab-SR
PO 30 – 90 minsSR: 6 hrs
PO: 12.5-25 mg
Every 6-12 hrs
Ziprasidone Cap,Injection
PO with foodIM only
6-8 hours
≤ 60 mins
PO: 20 mg
IM: 10 mg
Every 4-6 hrsMax IM 40mg/day
Do not use if recent MI or QTc prolong
Lexi-Drugs, 2017
http://www.alzbrain.org/pdf/handouts/5021.pdf
PO olanzapine and ziprasidone not ideal. *If use olanzapine suggest the ODT = orally disintegrating form
Case Vignette – Back to NH
78 yo female discharged back to nursing home after hip replacement surgery complicated by delirium. She returns to nursing home with the following new medications:
Enoxaparin 30 mg every 12 hours
Oxycodone 5/325 0.5 tablet every 4 hours PRN
Oxycodone 5/325 1 tablet every 6 hours PRN
Quetiapine 25 mg at bedtime
Docusate 100 mg at bedtime
Open discussion
Case Vignette
85+ year old AAF with a PMH of A.Flutter, TIA, hyperlipidemia, HTN and DM presents with altered mental status over the past month, escalating in the past few days. Recent behaviors include episodes of hollering, trying to throw self out of bed/wheelchair, and general disorientation.
HPI: 1 week ago was diagnosed and treated for UTI with ciprofloxacin 500 mg BID; U/A was sensitive to fluoroquinolones.1 month ago started on diltiazem and rivaroxaban for A.Flutter
• Focal seizures• Medically stable elderly • Preferred lamotrigine and levetiracetam• Second-line or equivocal: lacosamide
• Genetically mediated (idiopathic generalized)• Preferred lamotrigine and levetiracetam• Second-line: valproic acid, zonisamide, and topiramate
• Changes since 2001 Expert Opinion• In the elderly• Increase in preference for lamotrigine and levetiracetam• Decline in preference of phenytoin, oxcarbazepine,
gabapentin and carbamazepine
Shih JJ, et al. Epilepsy & Behavior 2017; in press
2016 Expert Opinion - Elderly
• Focal seizures• Medically stable elderly • Preferred lamotrigine and levetiracetam• Second-line or equivocal: lacosamide
• Genetically mediated (idiopathic generalized)• Preferred lamotrigine and levetiracetam• Second-line: valproic acid, zonisamide, and topiramate
• Changes since 2001 Expert Opinion• In the elderly• Increase in preference for lamotrigine and levetiracetam• Decline in preference of phenytoin, oxcarbazepine,
gabapentin and carbamazepine
Shih JJ, et al. Epilepsy & Behavior 2017; in press
Bryson AS, et al. J Pharm Pract Research 201545:349-56.
2015 Bryson AS, et al Australia:Focal seizures:• Proven Efficacy/1st line: carbamazepine
Reduction in Oral Clearance in ElderlyMedication Reduction in CL/F
(mL/h/kg) in elderly vs. young
Comments
Brivaracetam 8% Initial dose 25 mg BID, max 75 mg BID~ 50-59% ↑ in exposure in hepatic impair
Eslicarbazepine No change Mean age just under 70 years in one study
Felbamate 20-30% PK variability affected by enzyme inducers
Gabapentin 30-50% CL/F shows strong correlation with CrCl
Lacosamide 15-25% N/A
Lamotrigine 20-35% PK variability affected by drug interactions
Leveitracetam 20-60% PK variability affected by enzyme inducers
Oxcarbazepine 25-35% PK variability affected by enzyme inducers
Perampanel Insufficient data Study did include patients up to 74 years
Italiano D, et al. Clin Pharmacokinet 2013;52:627-45.
CL/F = oral clearance
Reduction in Oral Clearance in ElderlyMedication Reduction in CL/F
(mL/h/kg) in elderly vs. young
Comments
Pregabalin 30-50% CL/F shows strong correlation with CrCl
Retigabine 30% N/A
Rufinamide No Change Single dose study including patients 66-77 years
Tiagabine 30% PK affected by enzyme inducers
Topiramate 20% PK affected by enzyme inducers
S-Vigabatrin 50-90% Based on a single-dose study that included elderly patients with renal impairment
Zonisamide No change Study inclusion mean age just under 70 YearsPK variability affected by enzyme inducers
Italiano D, et al. Clin Pharmacokinet 2013;52:627-45.
CL/F = oral clearance
Renally Cleared
It is important to calculate creatinine clearance with the following AEDs:• Eslicarbazine• Gabapentin• Lacosamide• Levetiracetam • Pregabalin• Topiramate• Zonisamide
• Minor enzyme inhibitors• Valproic Acid – UGT (low)
English BA, et al. Curr Psychiatry Rep 2012;14:376-90
Therapeutic Drug Monitoring
Drug PHT PB VPA CBZ
Therapeutic Range USA
10-20 mg/L*Free: 1-2 mg/L
15-40 mg/L
50-100 mg/L
4-12 mg/L
RangeCanada
40-80 umol/LFree: 4-8 umol/L
60-160 umol/L
350 – 700 umol/L
20-50 umol/L
Order a phenobarbital level to monitor primidone (range 5-12 mg/L; 20-48 umol/L) as roughly 15-25% metabolized to PBLevels are not indicated for:• Levetiracetam• Oxcarbazepine• Lamotrigine• Topiramate
• HLAB*1502 was associated with CBZ induced SJS/TEN 92.3% (24/26) vs 11.9% of controls OR 89 95CI 19.25-413.83• 46.7 % (7/15) phenytoin • 33% of VPA (1/3) and of LMT (2/6)• 0% of PB, gabapentin or levetiracetam induced
• More recent study in Han Chinese found also associated with SJS/TEN:• oxcarbazepine (OR= 80.7, 95%CI 3.8-1714, p=<0.005) • phenytoin (OR= 5.1, 95% CI 1.8-15.1, p=<0.005)• lamotrigine (OR= 5.1, 95% CI 0.8-33.8, p=0.127)
Kwan PKL, et al. Hong Kong Med J 2014 20(7)Supp 7:S16-18.
AED Black Box WarningsMedication Black Box Warning
Carbamazepine Serious rash and HLA-B*1502 alleleAplastic anemia and agranulocytosis
VPA HepatotoxicityPancreatitis
LMT Serious rash
Vigabatrin Vision loss – can cause permanent bilateral concentric constriction of the visual field in ≥30% of patients; tunnel vision can occur, can damage central retina, reduce visual acuity. Vision tests at baseline, within 4 weeks of initiation, at minimum every 3 months, and 3-6 months after discontinuation.Do not use with other medication than cause retinopathy or glaucoma
Perampanel Psychiatric and Behavioral Disturbances
• Bryson et al. recommends a minimum of 2 years of seizure-free
• Taper slowly over months
Bryson et al. J Pharm Pract Research 2015;45:349-56.
AED Case VignettesEvaluate a given antiepileptic regimen in an older adult for efficacy and toxicity.
Case Vignette
85+ year old AAF with a PMH of A.Flutter, TIA, hyperlipidemia, HTN and DM presents with altered mental status over the past month, escalating in the past few days. Recent behaviors include episodes of hollering, trying to throw self out of bed/wheelchair, and general disorientation.
HPI: 1 week ago was diagnosed and treated for UTI with ciprofloxacin 500 mg BID; U/A was sensitive to fluoroquinolones.1 month ago started on diltiazem and rivaroxaban for A.Flutter
Head CT Impression:• No CT evidence of acute intracranial abnormality.Phenytoin level• Admission 29.7 mg/L [118.8 umol/L] at 12:46 pm• Day 3 at 6:00 am 20.1 mg/L [80.4 umol/L] • Day 7 11.6 mg/L [46.4 umol/L]Free Phenytoin • Day 3 at 12 pm 3.9 mg/L [15.6 umol/L]• Day 7 1.5 mg/L [6 umol/L]
Phenytoin vs. Free Phenytoin
mol/L120
100
80
60
40
20
mol/L16
12
8
4
Role of Free PHT Monitoring
• Phenytoin is 90% bound to albumin
• Free phenytoin crosses the BBB and can cause toxicity
• Symptomatic phenytoin toxicity can be experienced even at “normal” PHT levels in the presence of hypoalbuminemia and hyperbilirubinema
• If free PHT levels not available, check albumin levels and calculate a corrected PHT level
Robertson K, et al. BMJ Case Rep 2013. doi:10.1136/bcr-2012-008023; http://www-ncbi-nlm-nih-gov.proxy.library.vcu.edu/pmc/articles/PMC3618739/pdf/bcr-2012-008023.pdf
MAJOR Substrate of CYP2C19, CYP2C9 and minor CYP3A4Inducer of 2B6, 2C19, 2C8, 3A4, P-glycoprotein, UGT1A1
Case Vignette
• 84 year old F with a PMH seizures, hyperlipidemia, diabetes, HTN, and arthritis is develops a pulmonary embolism during hospitalization for an upper respiratory infection
• Current medications:• Phenobarbital 34. BID• Phenytoin 300 mg daily alternating with 400 mg daily• Pravastatin 40 mg at bedtime• Lisinopril 10 mg daily• Pioglitazone 15 mg daily• Acetaminophen 650 mg TID
• What oral anticoagulant do you recommend?
Phenytoin & Phenobarbital: Interactions with Anticoagulants
Metabolism Combine with Phenobarbital?
Combine with Phenytoin?
Warfarin MAJOR CYP2C9minor CYP3A4
↓ INR ↑ INR↑ PHT levels & toxicity*
NOACs
Dabigatran Primarily Pgp Avoid
Rivaroxaban MAJOR CYP3A4 Avoid Avoid
Apixiban MAJOR CYP3A4 Avoid Avoid
Edoxaban Primarily Pgp Monitor
PHT: CYP2C9 inducer, CYP3A4 inducer; Pgp Inducer PB: CYP2C9 inducer; CYP3A4 inducer* Reports of doubling of PHT levels
A 67 year old with a history of epilepsy has been treated with lamotrigine 100 mg BID for “years”. Recently has been having breakthrough seizures. Divalproex Na has been added to his regimen. What do you recommend?
A. Continue lamotrigine 100 mg BID
B. Increase lamotrigine to 200 mg BID
C. Decrease lamotrigine to 50 mg BID
D. Discontinue lamotrigine
Case Vignette
66 year old female with a PMH of seizures and bipolar disorder. Weight 66 kg1. Divalproex Na ER 500 mg Take 2 tab PO bedtime2. Famotidine 20 mg Take 1 tab PO every 12 hours3. Metoprolol tartrate 25 mg 1 tab PO every 12 hours
VPA level on admission undetectable
VPA vs Free VPAumol/L1050
700
350
Umol/L140
105
70
35
VPA Weight-based Dosing
• NOT ideal for the elderly!
• For this patient: 66 kg x 15 mg/kg = 990 mg
• Elderly should start• 125 mg TID or 250 mg BID
VPA Adverse Effects
• GI symptoms – diarrhea• Less with the enteric-coated (over immediate release) and
even less with ER (entended-release) formulation
• Hyponatremia• Thrombocytopenia• Tremor• Peripheral edema (in combination with antipsychotics
most reports with concurrent risperidone)• If experience altered mental status check an ammonia
level hyperammonemia encephalopathy • VPA is contraindicated in persons with Urea Cycle Disorders
and significant hepatic dysfunction
VPA-induced Hyponatremia
VPAThrombocytopenia
VPA-induced Thrombocytopenia
Case Vignette
A 64 year old patient admitted for elective knee replacement surgery.
Home medications included: lisinopril 10 mg daily, calcium 500 mg TID, diclofenac 75 mg BID, divalproex Na 250 mg TID.
Has been seizure free for over 9 months (Level on admission 68 mg/L [476 umol/L]).
During hospitalization develops hospital-acquired pneumonia and is started on an antibiotic.
3 days later she has a seizure. Repeat VPA level 22 mg/L [154 umol/L]). Which antibiotic were they started on?
Case Vignette
A 64 year old patient admitted for elective knee replacement surgery. Home divalproex Na 250 mg TID. Has been seizure free for over 9 months (Level on admission 68 mg/L [476 umol/L]). 3 days later she has a seizure. Repeat VPA level 22 mg/L [154 umol/L].
Which antibiotic were they started on?
A. Vancomycin
B. Meropenem
C. Levofloxacin
D. Piperacillin/tazobactam
VPA + Carbapenem Interaction
Antibiotic VPA level Pre-CBPM
VPA level during CBPM
% decrease P-value
Ertapenem (n=9) 66.5 ± 24.5~465
20.1 ± 15.7~140
72 ± 17 < 0.05
Imipenem/cilastatin(n=17)
62.9 ± 16.3~440
36.1 ± 16.2~252
42 ± 22 < 0.05
Meropenem (n=26) 53.1 ± 18.1~ 371
16.9 ± 11.8~118
67 ± 19 < 0.05
Total (n=52) 58.6 ± 19.2~410
23.7 ± 16.3 ~166
60 ± 23 < 0.05
Wu, C-C, et al. Ther Drug Monit 2016;38:587-92.
CBPM = carbapenem
LevetiracetamA 75 + year old admitted to psychiatry for new onset manic symptoms. Started on new meds VPA and Olanzapine, but was refusing most doses. On day 14 of admission developed new-onset partial-complex seizures.
Labs: Na = 137; glucose = 120 mg/dL [6.7 mmol/L]; BUN 6 mg/dL[2.14 mmol/L] ; SCr = 0.53 mg/dL [46.9 umol/L]; CrCl = 40 mL/min; Weight = 47 kg
Plan: -Transfer to NSICU under neurology service-Obtain prolonged video EEG-Start levetiracetam 1500mg bid-Check CXR, TSH, LFT'sDo you agree with this plan?
Levetiracetam Neuropsychiatric Adverse Effects • Anyone have any experience to share?
Levetiracetam
• Psychiatric ADEs
• Mania
• Psychosis
• OCD
• Rage
• Irritability
• Aggression
• Depression/Suicidality
Park EM, et al Psychosomatics 2014;55(1):99-100; Molokwu OA, Epilepsy Behav Case Rep. 2015;4:79-81. Fujikawa M, et al J Child Neurol 2015;30(7):942-4; Aggarwal A, et al. ProgNeuropsychopharmacol Biol Psychiatry 2011;35(1):274-5. Mula M, et al. Neurology 2003;61(3):124-32.
Elderly Case Reports
• A 73 yo AAM with stage 4 kidney disease was prescribed levetiracetam 500 mg BID for partial-complex seizures. New onset depression within 5 months; resolved within 4 weeks of discontinuation
• A 92 year old CF with CKD and new onset partial seizure was started on levetiracetam 500mg once daily. Depression symptoms noted within 5 weeks; improvement in mood and cognition within 8 days of discontinuation
Vande Griend JP, et al. Am J Geriatr Pharmacother2009;7(5):281-4
Brivaracetam vs Levetiracetam
• Like levetiracetam, brivaracetam also includes a warning regarding psychiatric adverse reactions including psychotic symptoms, irritability, depression, aggression, and anxiety
• Unlike levetiracetam, brivaracetam is hepatically cleared and has CYP drug interactions
Case Vignette
90 + year old with a history of seizures is currently treated with
• PR interval prolongation which may result in irregular heart beat, syncope
• Caution in patients with a cardiac conduction abnormality (2nd degree AV block), are taking drugs that prolong PR interval, or in myocardial infarction or heart failure
• If at risk check a baseline ECG and when steady state is achieved.
Lacosamide prescribing information 2008www.pixabay.com
• A 68 year old with a history of epilepsy that has been controlled on carbamazepine but has begun to experience leukopenia. Team wants to switch her off CBZ and transition to levetiracetam.
• Current medication list includes: • Amlodipine 10 mg daily• Diazepam 5 mg at bedtime• Lamotrigine 200 mg BID• Simvastatin 40 mg at bedtime• Oxycodone SR 20 mg every 12 hours
• What concern(s) do you have?
Carbamazepine
• A 68 year old with a history of epilepsy that has been controlled on carbamazepine but has begun to experience leukopenia. Team wants to switch her off CBZ and transition to levetiracetam.
• Current medication list includes: • Amlodipine 10 mg daily reduce dose?
• Diazepam 5 mg at bedtime reduce dose
• Lamotrigine 200 mg BID reduce to 100 mg BID
• Simvastatin 40 mg at bedtime reduce dose
• Oxycodone SR 20 mg every 12 hours reduce dose
Carbamazepine
• Carbamazepine is an inducer of • CYP1A2
• CYP2B6
• CYP2C9
• CYP2C19
• CYP3A4
• UGT
• P-gp
Questions??Neurology Update
Author: Ericka L. Crouse, PharmD, BCPP, BCGP, FASHP
Affiliation: Virginia Commonwealth University Health System